Elsevier

Experimental Neurology

Volume 207, Issue 1, September 2007, Pages 75-84
Experimental Neurology

Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation

https://doi.org/10.1016/j.expneurol.2007.05.019Get rights and content

Abstract

Individuals with spinal cord injury (SCI) are highly susceptible to infection. This post-traumatic immune suppression is thought to occur via alterations in sympathetic nervous system (SNS) or hypothalamic–pituitary–adrenal (HPA) axis function. Normally, the HPA axis and SNS help coordinate proper immune function. After SCI, the HPA axis becomes activated and descending input to sympathetic preganglionic neurons (SPNs) is impaired. Because lymphoid organs are innervated by SPNs distributed throughout the thoracolumbar spinal cord, we predicted level-dependent immune suppression after SCI due to activation of the HPA axis and loss of descending input to SPNs. We tested this hypothesis by measuring indices of HPA (circulating corticosterone; CORT) and SNS function (norepinephrine (NE) in spleen) as well as antigen-specific antibody synthesis against an exogenous non-self protein following high- or low-level SCI. Using a mid-thoracic (T9) spinal contusion injury model, we found that CORT was elevated after SCI with aberrant patterns of diurnal CORT synthesis evident through at least the first 24 h post-injury. However, splenic NE and antibody synthesis were similar to uninjured controls. Injury severity did not change these parameters. Indeed, CORT, NE and antibody synthesis were similar after T9 contusion or transection SCI. In contrast, high-level SCI (T3) caused sustained increases in CORT and splenic NE along with impaired antibody synthesis and elevated splenocyte apoptosis. The immunosuppressive effects of T3 SCI were caused by NE acting at β2-adrenergic receptors (β2AR) and could be reversed using β2AR blockers. Interestingly, impaired antibody after T3 SCI could be mimicked after T9 SCI with a β2AR agonist. These data illustrate the immunosuppressive effects of the SNS after high-level SCI and indicate that immune deficits may be overcome using β-blockers.

Introduction

Clinical data show that human spinal cord injury (SCI) is accompanied by profound immunological impairment (Cruse et al., 1993, Nash, 2000). Undoubtedly, immune dysfunction after SCI contributes to the significant increase in mortality caused by septicemia, diseases of the lung (e.g., pneumonia), gastrointestinal tract or urinary system (DeVivo et al., 1989). SCI-induced deficiencies in supraspinal control of the sympathetic nervous system (SNS) or hypothalamic–pituitary–adrenal (HPA) axis have long been suspected, but never proven, as mechanisms of post-traumatic immune suppression (Cruse et al., 1996, Nash, 2000).

Activation of the HPA axis causes release of cortisol (humans) or corticosterone (CORT; rodents) from the adrenal cortex into the bloodstream. High or sustained levels of CORT suppress antibody production, cytokine synthesis and leukocyte proliferation (Munck et al., 1984, Barnes, 1998, Moraska et al., 2000). In humans, urinary cortisol remains elevated for months after SCI (Campagnolo et al., 1999) suggesting prolonged dysregulation of HPA function. Activation of the SNS causes the release of norepinephrine (NE). In spleen and lymph nodes, noradrenergic nerves synapse on T and B cells (Felten et al., 1987, Felten and Olschowka, 1987). This “hardwiring” between the spinal cord and lymphoid tissue ensures proper immune function. Indeed, depletion of noradrenergic neurons suppresses antibody synthesis (Kohm and Sanders, 1999). This deficit is overcome by activating B cells in the presence of β2-adrenergic receptor (β2AR) agonists (e.g., terbutaline) (Podojil and Sanders, 2003). However, repeated or prolonged exposure of B cells to NE or other β2AR agonists is immunosuppressive (Melmon et al., 1974, Keller et al., 1983, Maisel, 1994, Harris et al., 1995, Woiciechowsky et al., 1998, Prass et al., 2003).

HPA/SNS responses are coordinated in the spinal cord via supraspinal projections and by afferent feedback from the periphery to sympathetic preganglionic neurons (SPNs) (Hayes et al., 1991, Taylor and Weaver, 1993). SPNs found throughout the thoracic spinal cord (T3–13; Strack et al., 1989, Cano et al., 2001) influence immune function through post-ganglionic noradrenergic projections to spleen (Wan et al., 1993) and adrenal cortex (Bloom et al., 1988, Engeland, 1998). Because SPNs are influenced by descending input from the brain, we predicted that high-level SCI would cause greater dysfunction of the HPA axis and SNS and subsequently, greater immunological impairment than lower level SCI. To test this, mice were subjected to high (T3) vs. mid-thoracic (T9) SCI; after which, circulating CORT, splenic NE and antigen-specific antibody responses were measured as indices of HPA activation and SNS and immune function, respectively. The data show that only after T3 SCI is splenic NE elevated and immune function suppressed. Moreover, the immunological impairment that occurs in T3 SCI mice can be overcome by pharmacological blockade of β2ARs, implicating NE in post-traumatic immune suppression. These studies are of potential clinical significance and could dramatically influence the design of prophylactic or therapeutic vaccines. Indeed, the ability to eradicate extracellular pathogens (Luster et al., 1993, Robbins et al., 1995) or mount an immune response against CNS proteins (e.g., myelin inhibitory proteins) (Huang et al., 1999, Hauben et al., 2001) requires the coordinated activity of T and B cells, dendritic cells and their associated cytokine networks. Here we show that each of these parameters is affected by SCI in a level-dependent fashion.

Section snippets

Mice

Adult pathogen-free C57BL/6 female mice (6–8 weeks old; 16–21 g) were purchased from Taconic Laboratories (Germantown, NY). All experimental procedures described below were approved by the Animal Review Committee at Ohio State University and are in accord with the US Department of Health, Education, and Welfare.

Spinal cord injury

A total of 82 mice received a spinal cord injury (SCI) as described below. Mice were anesthetized (i.p.) with a cocktail of ketamine (80 mg/kg)/xylazine (40 mg/kg), then given

SCI activates the HPA axis but disrupts circadian CORT synthesis

Previously, we demonstrated SCI-induced elevations of serum CORT in a rat model of SCI (Popovich et al., 2001). Here, we extend those findings to mice using a similar model of spinal contusion injury. Specifically, serum CORT was elevated in T9 SCI mice by 1 day post-injury (dpi), with levels returning toward baseline by 3 dpi (Fig. 1A). To determine whether SCI affected the circadian regulation of circulating CORT, sera were obtained from T9 spinal contusion-injured mice at regular intervals

Discussion

Here we show that immune suppression after SCI is level dependent and involves NE acting at β2ARs. Indeed, only in mice with high-level (T3) SCI was the concentration of splenic NE increased and antibody synthesis decreased relative to sham-injured or T9 SCI mice. Although the precise mechanism of immune suppression remains unclear, our results implicate aberrant β2AR-mediated signaling in lymphocytes. Indeed, only in T3 SCI mice was increased splenocyte apoptosis noted and immune suppression

Acknowledgments

The authors thank Ming Wang, Zhen Guan, Pat Walters, Violeta McGaughy and Susan Moseley for their technical assistance. The authors also thank Daniel Ankeny, Kristina Kigerl and Dana McTigue for their critical review. Funding was provided by NIH T32 AI55411 (KML), NIH AI37326 (VMS), NIH NS047175 (PGP) and P30-NSO45758.

References (57)

  • D.I. Campagnolo et al.

    Alteration of immune system function in tetraplegics. A pilot study

    Am. J. Phys. Med. Rehabil.

    (1994)
  • D.I. Campagnolo et al.

    Impaired phagocytosis of Staphylococcus aureus in complete tetraplegics

    Am. J. Phys. Med. Rehabil.

    (1997)
  • D.I. Campagnolo et al.

    Adrenal and pituitary hormone patterns after spinal cord injury

    Am. J. Phys. Med. Rehabil.

    (1999)
  • G. Cano et al.

    Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing

    J. Comp. Neurol.

    (2001)
  • J. Chastre et al.

    Ventilator-associated pneumonia

    Am. J. Respir. Crit. Care Med.

    (2002)
  • J.M. Cruse et al.

    Neuroendocrine-immune interactions associated with loss and restoration of immune system function in spinal cord injury and stroke patients

    Immunol. Res.

    (1992)
  • J.M. Cruse et al.

    Decreased immune reactivity and neuroendocrine alterations related to chronic stress in spinal cord injury and stroke patients

    Pathobiology

    (1993)
  • J.M. Cruse et al.

    Immune system-neuroendocrine dysregulation in spinal cord injury

    Immunol. Res.

    (1996)
  • A.O. Davies et al.

    Agonist-promoted high affinity state of the beta-adrenergic receptor in human neutrophils: modulation by corticosteroids

    J. Clin. Endocrinol. Metab.

    (1981)
  • A. del Rey et al.

    Sympathetic abnormalities during autoimmune processes: potential relevance of noradrenaline-induced apoptosis

    Ann. N. Y. Acad. Sci.

    (2003)
  • M.J. DeVivo et al.

    Cause of death for patients with spinal cord injuries

    Arch. Intern. Med.

    (1989)
  • W.C. Engeland

    Functional innervation of the adrenal cortex by the splanchnic nerve

    Horm. Metab Res.

    (1998)
  • S. Ewig et al.

    Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury. Incidence, risk factors, and association with ventilator-associated pneumonia

    Am. J. Respir. Crit. Care Med.

    (1999)
  • S.Y. Felten et al.

    Noradrenergic sympathetic innervation of the spleen: II. Tyrosine hydroxylase (TH)-positive nerve terminals form synapticlike contacts on lymphocytes in the splenic white pulp

    J. Neurosci. Res.

    (1987)
  • D.L. Felten et al.

    Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp

    J. Neurosci. Res.

    (1987)
  • E. Hauben et al.

    Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: comparison with other myelin antigens

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • K. Hayes et al.

    Evidence for descending tonic inhibition specifically affecting sympathetic pathways to the kidney in rats

    J. Physiol.

    (1991)
  • W.E. Hurford et al.

    Splenic contraction, catecholamine release, and blood volume redistribution during diving in the Weddell seal

    J. Appl. Physiol.

    (1996)
  • Cited by (164)

    • Infections and spinal cord injury: Covid-19 and beyond

      2022, Diagnosis and Treatment of Spinal Cord Injury
    View all citing articles on Scopus
    View full text